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#apaperaday: A rare complex structural variant of novel intragenic inversion combined with reciprocal translocation t(X;1)(p21.2;p13.3) in Duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: A rare complex structural variant of novel intragenic inversion combined with reciprocal translocation t(X;1)(p21.2;p13.3) in Duchenne muscular dystrophy

It is complex DMD variant day, with a paper from Wang et al (different from the Wang et al monozygotic triplet paper earlier this week) on a complex translocation/inversion published in @WorldMuscleSoc journal Neuromuscular disorders DOI: 10.1016/j.nmd.2024.04.003

In most cases Duchenne is caused by the deletion (2/3) or duplication (1/10) of one or more exons while in about 1/4 there is a small mutation within an exon or the splice sites. However, additional variants are possible and researchers in China do a good job publishing on these.

Authors here describe a 10 year old patient who had all the characteristics of Duchenne: waddling gate since 2-3 year, frequent falls, loss of ambulation at age 9, speech problems and CK was elevated >10k U/L. MRI analysis showed fatty infiltration.

Muscle histology showed variation in fiber size, centrally located nuclei, fibrosis & adiposis. Dystrophin staining was negative, but no mutation could be found with MLPA (deletions/duplications) or NGS (small mutations) nor were variants found in other muscular dystrophy genes.

RNA analysis revealed that exon 59-79 were absent. Authors then performed nanopore sequencing (of very long pieces of DNA) and this revealed a very complex rearrangement (see image). There was a translocation between chromosome 1 & chromosome X, involving intron 67 of the dystrophin gene.

However, there was also an inversion of exon 63-67 and a small deletion on chromosome 1. This explained the Duchenne pathology and also the cognitive aspects (mental retardation) as these patients cannot make any of the dystrophin isoforms.

The boy’s mother also had muscle weakness, cardiomyopathy that became apparent during pregnancy and mental retardation. CK was mildly elevated. The mother died at age 37 due to cardiomyopathy so obtaining new DNA for long read sequencing was not possible.

Authors discuss that in this case even mRNA analysis was not sufficient to find the mutation, although mRNA analysis did point towards something being wrong. They also discuss that due to size of the dystrophin gene (humongous) it is more sensitive to large rearrangements.

Many of the dystrophin introns contain repetitive elements which make them more prone to deletions, duplications and also translocations. Finally authors discuss the mother of the patient, who also had mental retardation and heart problems and mild muscle dystrophy.

They argue that most likely she also carried the mutation. However, in females a translocation will lead to full blown Duchenne (as the only cells surviving X-inactivation are those where the wild type X chromosome will be inactive).

We can only speculate: the woman had mental retardation and cardiomyopathy but the muscle pathology was not that severe. It is possible she was a mosaic with the translocation present in brain and heart and the germline cells but not in the muscles.

However, this is purely speculation. I appreciate the authors for elucidating this complicated variant and reporting on it. Even though this is interesting from a genetic perspective, the story behind it is sad and my heart goes out to this family.